Faculty of Medicine

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Association of CURB-65 (Confusion, Urea, Respiratory Rate, Blood Pressure) with Mortality of Patients with Severe Community-Acquired Pneumonia
(Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, 2009)
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Background. Severe community-acquired pneumonia (sCAP) is serious, life-thretening condition, with high mortality rate. Scoring systems for disease severity are used for predicting mortality in patients with pneumonia. Objective of this study was to identify the parameters of CURB-65 score that have higher association with mortality in patients with severe CAP. Material and methods. One hundred and two patients with community-acquired pneumonia were enrolled in the study. The study was conducted at the Intensive Care Department of the Clinic for Infectious Diseases and Febrile Conditions-Skopje. Demographic, clinical and biochemical parameters were analyzed and CURB-65 was calculated in each patient at admission. Predictors were identified using logistic regression analysis. Receiver Operating Characteristic Curve (ROC) was constructed for assessing discriminative power of analyzed parameters. Results. CURB-65 identified severe CAP in 32 (31,4%) patients, with overall mortality rate of 62,5%. Confusion, respiratory rate > 30/min and urea > 7mmol/L had significant association with the mortality. Conclusion. CURB-65 is a simple tool that can identify patients with severe CAP and can be used for early prediction of patients mortality.
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Prognostic significance of the HPV status in early stage cervical carcinoma
(Macedonian Academy of Sciences and Arts, 2006-09)
Kubelka-Sabit, Katerina
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Prodanova, Irina
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Yashar, Genghis
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Zografski, George
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Aims: In order to evaluate their prognostic significance, the parameters of the human papilloma virus (HPV) status were correlated to the lympho-nodal and tumor status, maximal diameter, minimal thickness of uninvolved stroma, histologic type, grade of differentiation, lympho-vascular space invasion, degree of lymphocytic inflammatory stromal reaction at the invasion front, age and the disease-free survival (DFS) of the patients with early stage invasive cervical carcinomas. Material and methods: 77 cases of cervical carcinomas, limited to the uterus, surgically treated and postoperatively irradiated, were selected for this retrospective study. HPV DNA status (presence and HPV type, type of hybridization signal and number of positive cells per sample) was evaluated using sensitive in situ hybridization detection kit with catalyzed signal amplification with biotinylated probes for types 6/11, 16/18 and 31/33 or 31/33/51. Results: The presence of HPV DNA was detected in 45 (58.4%) cases. Thirty-two (71.1%) showed positivity for HPV type 16/18, 8 (17.8%) for 31/33, whereas multiple infection was detected in (8.9%) 4 cases. Dot hybridization signal was found in 31 (68.9%), diffuse in 2 (4.4%) and mixed in 12 (26.7%) cases. More than five positive nuclei per sample were found in 37 (82.2%) of the cases. Only the presence of HPV was associated with absence of regional lymph node involvement, presence of moderate/abundant lymphocytic infiltration and longer 5 and 10-year DFS. Conclusions: According to our results, more extensive studies are needed to assess the real prognostic influence of the other parameters of HPV status in early stage cervical carcinomas.
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Small and large cell neuroendocrine carcinomas of the uterine cervix. A report of 10 cases.
(Springer, 2005-08)
Kubelka-Sabit, Katerina
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Plaseska-Karanfilska, Dijana
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Prodanova, Irina
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Yashar, Genghis
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Hadzi-Nicheva, Biljana
BACKGROUND: Small (SCC) and large cell (LCC) neuroendocrine carcinomas of the uterine cervix are rare and highly aggressive neoplasms. Their association with the integration of human papilloma virus (HPV) DNA of the types 16 or 18 has been documented in many studies. AIMS: The purpose of this study is to present the clinical, histopathological, immunohistochemical characteristics and the presence of HPV DNA in ten cases of SCCs and LCCs of the uterine cervix. METHODS: Seven patients with primary SCCs and three patients with LCCs of the uterine cervix were diagnosed at our department between 1989 and 2004. Clinical data were retrieved from the patients’ files and included age, recurrence and survival. Routinely processed operative and/or biopsy specimens were used for immunohistochemical stains and hybridization procedures. Primary antibodies against several epithelial, neuroendocrine, mesenchimal and proliferative markers were included. The presence of HPV DNA was assessed by conventional in situ hybridization (ISH) using probes for HPV 16/18 and 31/33/51 and polymerase chain reaction (PCR), using three primers (MY09/11, GP5+/GP6+, E6). Six of the patients were surgically treated. Postoperatively, four received chemo and/or radiotherapy, two rejected further treatment and one patient was lost to follow-up. The other four patients underwent conservative treatment due to advanced disease. RESULTS: The patients’ age ranged from 25 to 71 years. Histologically, the tumors showed trabecular, nesting or a sheet-like pattern, with areas of necrosis and frequent mitoses. Their neuroendocrine nature was confirmed by diffuse positive immunostaining for neuron-specific enolase and low-molecular weight cytokeratins. Focal positivity for chromogranin, synaptophysin and S100, together with pancytokeratin and EMA, was evident in the majority of the tumors. Their aggressive potential was confirmed by high Ki-67 proliferative index (50-90%). HPV types 16/18 were found in 4 tumors using ISH, and HPV 16 in additional 3, using PCR (type 16). 3 of the patients developed distant metastases and died 7-48 months after receiving partial or full treatment, while 6 are alive and without evidence of disease after 4-38 months. CONCLUSIONS: SCCs and LCCs are highly aggressive neoplasms. However, early diagnosis and combined therapy may improve survival in some patients. Although mainly a morphologic diagnosis, immunohistochemistry may help in the diagnosis of SCC and LCC.
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Ki-67 expression in the invasion front as an additional independent significant prognostic factor influencing reccurence in early stage cervical carcinomas.
(Springer, 2005-08)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Yashar, Genghis
INTRODUCTION: The attempts to determine the prognostic significance of biological markers and their relation to human papillomavirus (HPV) infection in cervical cancer have yielded controversial results. AIMS: The aims of this retrospective study were to correlate alterations of cell proliferation, growth, differentiation and apoptosis regulatory proteins in early stage cervical carcinomas with HPV infection, histopathological and clinical parameters, and to estimate their prognostic significance. METHODS: Expression of Ki-67, p53, mdm-2, bcl-2, c-erbB-2, EGFR protein, as well as estrogen and progesterone receptors was evaluated by immunohistochemistry in operative specimens of 83 patients with early stage cervical carcinoma. The results were assessed semiquantitatively in the surface area, center and invasion front of each tumor as a percentage of the immunostained cells and/or intensity of immunostaining for each protein. The presence of HPV was assessed by conventional in situ hybridization (ISH) technique and catalyzed reporter deposition signal amplification ISH using mixed biotinylated probes to identify types 6/11, 16/18 and 31/33 or 31/33/51. RESULTS: In our case series 73 patients had a tumor limited to the uterine cervix less than 4 cm in diameter (pT1b1), while 10 patients had larger neoplasms belonging to pT1b2 category. Pelvic lymph node involvement was found in 20 patients. During the follow-up period (range, 65 -181, mean, 121 months) recurrences were observed in 9 patients. The 5, 10 and 15-year disease-free survival rate was 92.7%, 90.8% and 86.6%, respectively. Among the 18 variables pelvic lymph node involvement (P=0.0008), tumor diameter (P=0.035), depth of stromal invasion (P=0.029), histotype (P=0.0009), grade (P=0.056), HPV DNA presence (P=0.056), HPV type (P=0.043), as well as bcl-2 (P=0.035), mdm-2 (P=0.051), EGFR (P<0.0001), and Ki-67 (P=0.031) expression in the tumor’s invasion front were identified as important predictive indicators of recurrence in the univariate analysis. Independent significant prognostic factors for disease-free survival in multivariate analysis were the histotype, HPV DNA presence and Ki-67 expression. CONCLUSIONS: The invasive front of carcinomas proved to be the most important area for tumor prognosis. In addition to the detection of HPV presence and morphological parameters, Ki-67 evaluation could be used in selecting appropriate therapeutical approaches in patients with early stage cervical cancer.
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Iimmunohistochemical expression of c-erbb-2 in early stage cervical carcinoma: Correlation with human papillomavirus infection and prognosis.
(Springer, 2003-09)
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Yashar, Genghis
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Kubelka-Sabit, Katerina
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Prodanova, Irina
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Zografski, George
Introduction: The attempts to determine the prognostic significance of c-erbB-2 oncoprotein expression (OPE) and its relation to human papillomavirus (HPV) infection in cervical cancer have yielded controversial. The aim of this study was to evaluate the patterns of c-erbB-2 OPE in early stage cervical carcinoma and to assess its prognostic value by exploring its relationships to various clinicopathological characteristics, HPV status and recurrence rate. Materials and methods: Radical hysterectomy specimens from 71 cervical carcinoma patients (pT1b1/1b2) were investigated immunohistochemically for c-erbB-2 presence. The c-erbB-2 score (range: 0-400) was determined in the surface area, center and invasion front of each carcinoma. CARD in situ hybridization was used for HPV detection. Results and conclusion: Strong c-erbB-2 OPE was detected in 21, 20, and 32 cases in the invasion front, center and surface area of the tumor, respectively. There was a significant difference in positive staining rate of c-erbB-2 between squamous cell, mixed carcinomas and adenocarcinomas (23%, 50% vs 83%, p=0.005). C-erbB-2 OPE was significantly higher in carcinomas with abundant than in tumors with less abundant peri-tumoral lymphocytic infiltration (36.5% vs 10.5%, p=0.032). In HPV positive carcinomas (41), c-erbB-2 was detected more frequently in type 31/33 versus type 16/18 lesions (75% vs 18.8%, p=0.002). No association was found between c-erbB-2 expression and recurrence rate, lymph node metastasis or any other clinicopathological variable investigated (age, tumor diameter, depth of invasion, grade, vascular invasion). Therefore, immunostaining for c-erbB-2 is unlikely to be of use as a prognostic indicator in early stage cervical carcinomas, while further study is warranted to examine relationships between HPV infection and c-erbB-2 OPE.
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Determination of estrogen, progesterone receptor and ki-67 immunoreactivity in early stage cervical carcinoma: Association with human papillomavirus infection and prognosis.
(Springer, 2003-09)
Yashar, Genghis
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
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Introduction: The predictive values of estrogen (ER) and progesterone receptor (PgR) status and cell proliferation kinetics in cervical carcinomas are still unsettled. The purpose of this study was to clarify the associations among ER/PgR status and Ki-67 expression and to determine their relationship to human papillomavirus (HPV) infection, recurrence rate and other clinicopathologic parameters (age, tumor diameter, depth of invasion, histotype, grade, vascular involvement, inflammatory infiltrate, lymph node status) in early stage cervical carcinomas. Materials and methods: ER, PgR and Ki-67 immunostaining was performed in 72 cervical carcinoma radical hysterectomy specimens (pT1b1/pT1b2). ER/PgR staining was scored in a semiquantitative fashion, while to evaluate the cell proliferation, the Ki-67 labelling index (LI) was assessed in the surface area, center and invasion front of each tumor. HPV status was determined by CARD in situ hybridization. Results and conclusion: ER positivity was detected in 11 (15%), while PgR positivity in 14 (20%) carcinomas. ER/PgR values were in correlation with Ki-67 LI in all three tumors' compartments (p<0.01). In contrast to ER/PgR status, Ki-67 LI was strongly associated with HPV infection (p<0.01). No relationship was found between PgR or Ki-67 immunoreactivity and either recurrence rate or any other clinicopathological variable investigated. Nevertheless, reduced ER expression was significantly associated with larger tumor diameter (p=0.04) and poor differentiation (p=0.03), as well as lymphovascular involvement (p=0.04) and lymph node metastases (p=0.02). These results suggest that ER, PgR and Ki-67 expression are closely related to neoplastic cell proliferation, probably induced by HPV infection. Their determination may provide additional prognostic information in early stage cervical carcinomas.
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Blood vessel invasion and inflammatory stromal reaction at the invasion front as additional significant prognostic factors in surgically treated patients with cervical carcinoma.
(Springer, 2001-09)
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Yashar, Genghis
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Veljanoska, Slavica
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Kubelka, Katerina
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Prodanova, Irina
Introduction: The objective of this study was to evaluate the prognostic significance of 23 clinical and histopathological variables in relation to disease-free (DFS) and overall survival (OS) in patients with early stage cervical carcinomas. Methods: A retrospective analysis of 237 patients with cervical carcinoma, undergoing radical hysterectomy and postoperative irradiation between 1988 and 1997 was conducted. The operative specimens were subjected to detailed and uniform histopathological work-up. The patients were staged according to the postoperative TNM classification of UICC (1997) guidelines. Mean follow-up time was 57 (18-124) months. Results: The 5 and 10-year OS rate was 80.8%, while DFS rates at 5 and 10 years were 76.8% and 75.5%, respectively. In multivariate analysis, blood vessel invasion, pelvic lymph node metastases, tumor diameter, inflammatory stromal reaction at the invasion front, and minimum thickness of uninvolved cervical stroma/parametrial extension, were independent and significant variables. The prognostic index, as an indicator of the patient's place in the prognostic spectrum, defined by the Cox regression model, was able to categorize the patients into three distinct risk groups. The 5-year DFS and OS rates of the low-, intermediate-, and high-risk groups were 97.5%, 86.3%, and 43.8%, vs. 98.8%, 84.5%, and 45.3%, respectively (P<0.0001). Conclusions: The prognostic index could be a sound basis for an appropriate planning of the following therapeutical strategy for the surgically treated patients with cervical carcinoma. The postoperative TNM classification should be modified, incorporating the blood vessel invasion and the inflammatory stromal reaction at the invasion front, as additional significant prognostic factors.
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Immunohistochemical study of phyllodes tumor of the breast
(Springer, 1999-09)
Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
Phyllodes tumor ('PT) is a rare, fibroepithelial breast neoplasm with unpredictable prognostic and controversial therapeutic aspects. Aims: The aim of this retrospective study is to evaluate Ki-67 and CD34 antigen expression, as well as estrogen (ER) and progesterone receptor (PgR) status in stromal cells, as additional diagnostic criteria in assessing different types of PT. Methods: Routinely processed, formalin-fixed and paraffin-embedded surgical specimens from 47 cases of PT were stained by immunoperoxidase technique using Ki-67, CD34, ER and PgR monoclonal antibodies. On the basis of histopathological criteria proposed by Azzopardi, 6 malignant, 12 borderline and 29 benign PT have been evaluated. The mean size of the tumour was 9.4 cm (range 2.8-20 era). During the follow-up period (mean 50, range 2-127 months), recurrences were observed in 8 patients (17%). Results: The proliferating index determined by Ki-67 antigen expression was significantly different between histologically benign PT (19%), borderline PT (25%) and malignant PT (50%). There was a difference of the human progenitor cell CD34 antigen expression in malignant PT (50%), borderline PT (50%) and benign PT (30%). As expected, the stromal cells in various types of PT were mostly ER negative and PgR positive. Conclusions: Our preliminary results suggest that CD34 positivity and high proliferative index of Ki-67 antigen in stromal cells are more frequently associated with high grade PT. Therefore, the immunohistochemical features could provide better discrimination between different PT types. The prognostic implications of these observations should be evaluated in additional studies.
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Paravaginal female adnexal tumor of probable Wolffian origin. A case report
(Springer, 1999-09)
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Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
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Stavrik, George
Female adnexal tumor of probable Wolffian origin (FATWO) is a rare neoplasm originating from mesonephric remnants. Approximately 50 cases have been reported, predominantly arising in broad ligament, mesosalpinx, ovarian hilus, and periadnexal region. Aims: The aim of this report is to present the clinical and pathological features of a FATWO occurring in paravaginal area. So far, there have been only two cases reported to occur at this site. Case report: The patient is a 23-year old, nuliparous female, presented with a painless fixed paravaginal tumor. In August 1995, explorative laparatomy was performed. Encapsulated ovoid, tumor, located between urinary bladder and vagina, tightly fixed to vaginal wall connective tissue, was found. The uterus and both adnexa appeared unremarkable. The tumor was removed and biopsy sample from left ovary was taken. The patient had had an uneventful post-operative course and she remained well, without evidence of recurrence, 42 months after laparatomy. Results: The tumor was a solid ovoid mass with smooth surface, measuring 6.7 x 5 x 3.7 cm. On sectioning, the neoplastic tissue was solid, soft, butter yellow in colour; multiple cysts varying up to 3 cm in diameter and hemorrhagic foci were also present. Microscopically, it was well circumscribed and surrounded by fibrous capsule, composed of tumor cells arranged in different patterns: solid, closely packed tubules, and microcystic. The histochemical and immunohistochemical features of the tumor were identical to other cases of FATWO reported in the literature. Conclusions: Although the majority of these tumors are benign, a few cases have shown definite low malignant potential, with metastases and recurrences developing after at least 6 to 16 years following radical surgery. The presented case indicates that in spite of the unusual location, FATWO must be recognized, ensuring a careful and prolonged follow-up.
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Ovarian mucinous cystadenoma with murale nodule of poorly differentiated squamous cell carcinoma. Report of a case
(Blackwell Publishing Ltd., 2008-10)
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Zografski, George
Background. Mural nodules associated with mucinous and serous tumors of the ovary may represent a reactive process, a benign tumor, or a malignant neoplasm. Thus, the prognosis of the ovarian tumor can be dramatically modified by the presence of this nodule. We report the clinicopathologic and immunohistochemical findings of a case of a mural nodule of anaplastic squamous cell carcinoma associated with ovarian mucinous cystic tumor. Case report. The patient was a 66-year-old postmenopausal woman (gravida 1, para 1) with a 6-month history of increasing abdominal fullness. An abdominal ultrasound revealed a multilocular left ovarian cyst with a solid component. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, the diagnosis of a mucinous cystadenoma with a focus of FIGO stage IC anaplastic carcinoma in the left ovary was made. The patient received six courses of chemotherapy; 3 months after completing chemotherapy, she developed rectosygmoidal wall metastases. Despite rectosygmoid resection and additional chemotherapy and radiotherapy, the disease persisted in the pelvis and the patient died 14 months after initial operation. The primary tumor nodule as well as metastatic rectosygmoid tumors were studied by conventional and immunohistochemical methods. Results. The left ovarian tumor measured 8.5 x 8 x 6 cm. On cut sectioning, it was multilocular with a solid 4.5 x 4 x 3 cm mural nodule. Microscopically, the cyst wall was predominantly lined with benign mucinous epithelium, with rare foci of endometriosis found in smaller locules. The solid area of the mural nodule showed nests of spindle or polygonal highly malignant cells with admixed inflammatory cells. Necrosis and hemorrhage were also present. The ovarian capsule was invaded by the pleomorphic tumor cells. In favor of a diagnosis of anaplastic carcinoma were poor circumscription of the nodule with lymph-vascular involvement and absence of a prominent inflammatory reaction with multinucleated giant cells of the epulis type. In addition, the metastatic rectosygmoid tumor showed poorly differentiated squamous cell carcinomatous features. Immunohistochemically, the atypical cells of the nodule as well as a metastatic tumor were uniformly positive for epithelial markers such as pan-cytokeratin, high-molecular weight cytokeratin, cytokeratin 7 and epithelial membrane antigen, negative for carcinoembryonic antigen and focally weakly positive for vimentin. Many of these cells were also immunoreactive for p53 (80-90%) and Ki-67 (40-50%). Conclusion. The occurrence of ovarian mucinous cystic tumor with mural nodule of poorly differentiated squamous cell carcinoma is evidently very uncommon, because we have not found a similar case in the literature. The malignant nodules composed of sarcoma or anaplastic carcinoma such as in our case are associated with an unfavourable outcome and must be distinguished from other sarcoma-like nodules that may also occur in the wall of mucinous ovarian tumours. Therefore, the implementation of strict morphologic criteria supplemented by immunohistochemistry aids in the sometimes difficult differential diagnosis among these types of mural nodules.

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